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Zhang, Yanyu
Publications (4 of 4) Show all publications
Zhang, Y., Valsala Madhavan Unnithan, R., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., . . . Olsson, A.-K. (2019). TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells. The FASEB Journal, 33(7), 7822-7832
Open this publication in new window or tab >>TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells
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2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 7, p. 7822-7832Article in journal (Refereed) Published
Abstract [en]

Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor-associated factor (TRAF) family member-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1) is a previously unknown mediator of platelet-induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet-induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet-induced activation of the NF-kappa B subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet-induced NF-kappa B signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.-Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.-K. TANK-binding kinase 1 is a mediator of platelet-induced EMT in mammary carcinoma cells.

Keywords
platelets, cancer, TBK1, NF-kappa B, metastasis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392047 (URN)10.1096/fj.201801936RRR (DOI)000476234700004 ()30912981 (PubMedID)
Funder
Swedish Research Council, 2016-03036Swedish Cancer Society, CAN 2017/522Swedish Society of Medicine, SLS-683851
Note

Ragaseema Valsala Madhavan Unnithan and Anahita Hamidi contributed equally to this work.

Jessica Cedervall and Anna-Karin Olsson contributed equally to this work.

Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Cedervall, J., Dragomir, A., Saupe, F., Zhang, Y., Ärnlöv, J., Larsson, E., . . . Olsson, A.-K. (2017). Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.. Oncoimmunology, 6(8), Article ID e1320009.
Open this publication in new window or tab >>Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed) Published
Abstract [en]

Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

Keywords
Cancer, DNase I, GSK484, kidney injury, neutrophil extracellular traps
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-329754 (URN)10.1080/2162402X.2017.1320009 (DOI)000408961700006 ()28919990 (PubMedID)
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2019-04-02Bibliographically approved
Cedervall, J., Zhang, Y., Huang, H., Zhang, L., Femel, J., Dimberg, A. & Olsson, A.-K. (2015). Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals. Cancer Research, 75(13), 2653-2662
Open this publication in new window or tab >>Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
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2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed) Published
Abstract [en]

Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-259098 (URN)10.1158/0008-5472.CAN-14-3299 (DOI)000357334700008 ()26071254 (PubMedID)
Funder
Swedish Cancer Society, 11 0653Swedish Research Council, 2010-6903-75363-44, 2012-77PK-22157-01-2
Available from: 2015-07-28 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
Cedervall, J., Zhang, Y., Ringvall, M., Thulin, Å., Moustakas, A., Jahnen-Dechent, W., . . . Olsson, A.-K. (2013). HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment. Angiogenesis, 16(4), 889-902
Open this publication in new window or tab >>HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment
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2013 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 4, p. 889-902Article in journal (Refereed) Published
Abstract [en]

Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFR beta. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.

Keywords
Platelets, Angiogenesis, HRG, Metastasis, EMT
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-209153 (URN)10.1007/s10456-013-9363-8 (DOI)000324326900013 ()
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2018-01-11Bibliographically approved
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